Methods and compositions for treating heart conditions

ABSTRACT

The disclosure provides methods and compositions for treating heart conditions. In particular, the disclosure provides compositions comprising lithium, or a salt thereof, either alone or in combination with at least one additional anti-arrhythmia agent, and methods for treating heart conditions using such compositions.

BACKGROUND

There are many types of heart disease, and each one has its own symptomsand treatment. Lifestyle changes and medicine can make a huge differencein improving a subject's health. One type of heart disease is anarrhythmia (when the heart has an irregular beating pattern). Seriousarrhythmias can often develop from other heart problems, but may alsohappen on their own.

Treatment of arrhythmia depends on the type and severity of thearrhythmia. In some cases of arrhythmia, no treatment is necessary.Treatment options can include: medications, lifestyle changes, invasivetherapies, electrical devices, and/or surgery. Some anti-arrhythmicmedications are extremely toxic, and thus are very infrequently used forthe treatment of arrhythmias, and even then can only be used for a shorttime due to the toxicity. Thus, there is a need in the art to developimproved methods, compositions, and therapies for treating cardiacarrhythmias.

SUMMARY

The disclosure provides methods and compositions for treating heartconditions. In particular, the disclosure provides compositionscomprising lithium, or a salt thereof, either alone or in combinationwith at least one additional anti-arrhythmia agent, and methods fortreating heart conditions using such compositions.

In one aspect, the disclosure provides a method for treating and/orpreventing a heart condition, comprising administering an effectiveamount of lithium, or a salt thereof, to a subject in need thereof.

In certain embodiments of this aspect, the heart condition is prematureventricular contraction (PVC), ventricular premature contraction (VPC),ventricular tachycardia, ventricular fibrillation, paroxysmalsupraventricular tachycardia, accessory pathway tachycardia, AV nodalreentrant tachycardia, supraventricular tachycardia, premature atrialcontractions, atrial fibrillation, atrial flutter, trigeminy, bigeminy,or Wolff-Parkinson-White (WPW) syndrome. In one embodiment, the heartcondition is premature ventricular contraction (PVC) or ventricularpremature contraction (VPC). In another embodiment, the heart conditionis atrial fibrillation.

In some embodiments, the lithium, or salt thereof, is lithium carbonate(Li₂CO₃), lithium sulfate (Li₂SO₄), lithium citrate (Li₃C₆H₅O₇), lithiumacetate (C₂H₃LiO₂), lithium bromide (LiBr), lithium chloride (LiCl),lithium orotate (C₅H₃LiN₂O₄), or lithium gluconate (C₆H₁₁LiO₇). Incertain embodiments, the effective amount of lithium comprises about 5mg to about 1800 mg per day, about 10 mg to about 1200 mg per day, about25 mg to about 600 mg per day, about 50 mg to about 550 mg per day,about 100 mg to about 500 mg per day, about 150 mg to about 450 mg perday, about 200 mg to about 400 mg per day, or about 250 mg to about 350mg per day. In one embodiment, the effective amount of lithium comprisesabout 300 mg per day.

In some embodiments, the effective amount of lithium results in alithium serum concentration in the subject in the range of about 0.01 toabout 1.2 mmol/L, about 0.02 to about 1.0 mmol/L, about 0.05 to about0.8 mmol/L, about 0.1 to about 0.6 mmol/L, about 0.2 to about 0.5mmol/L, about 0.25 to about 0.45 mmol/L, or about 0.1 to about 0.3mmol/L. In one embodiment, the effective amount of lithium results in alithium serum concentration in the subject in the range of about 0.1 toabout 0.3 mmol/L.

In some embodiments, the effective amount of lithium, or salt thereof,is administered as an extended release formulation. In certainembodiments, the effective amount of lithium, or salt thereof, isadministered one time per day, two times per day, three times per day,or four times per day.

In some embodiments, the effective amount of lithium, or salt thereof,is administered orally, parenterally, transdermally, topically,transmucosally, by inhalation, by suppository, by buccal delivery, bysublingual delivery, by ophthalmic delivery, or by injection(subcutaneous injection, subdermal injection, intramuscular injection,depot administration, or intravenous injection).

In some embodiments, the subject is treated for about 1 month, about 2months, about 3 months, about 4 months, about 5 months, about 6 months,about 7 months, about 8 months, about 9 months, about 10 months, about11 months, about 1 year, about 2 years, or more than 2 years. In certainembodiments, the subject is treated indefinitely.

In some embodiments, the method further comprises administering anadditional anti-arrhythmic agent. In certain embodiments, the additionalanti-arrhythmic agent is a sodium channel blocker (Class I), abeta-blocker (Class II), a potassium channel blocker (Class III), acalcium channel blocker (Class IV), and/or another anti-arrhythmicagent.

In some embodiments, the additional anti-arrhythmic agent is abeta-blocker and the beta-blocker is Acebutolol (SECTRAL®), Atenolol(TENORMIN®), Betaxolol (KERLONE®), Bisoprolol (ZEBETA®, ZIAC®),Carteolol (CARTROL®), Carvedilol (COREG®), Labetalol (NORMODYNE®,TRANDATE®), Metoprolol (LOPRESSOR®, TOPROL-XL®), Nadolol (CORGARD®),Nebivolol (BYSTOLIC®), Penbutolol (LEVATOL®), Pindolol (VISKEN®),Propanolol (INDERAL®), Sotalol (BETAPACE®), or Timolol (BLOCADREN®).

In another aspect, the disclosure provides a composition comprisinglithium, or a salt thereof, and an additional anti-arrhythmic agent.

In certain embodiments of this aspect, the lithium, or salt thereof, islithium carbonate (Li₂CO₃), lithium sulfate (Li₂SO₄), lithium citrate(Li₃C₆H₅O₇), lithium acetate (C₂H₃LiO₂), lithium bromide (LiBr), lithiumchloride (LiCl), lithium orotate (C₅H₃LiN₂O₄), or lithium gluconate(C₆H₁₁LiO₇).

In some embodiments, the additional anti-arrhythmic agent is a sodiumchannel blocker (Class I), a beta-blocker (Class II), a potassiumchannel blocker (Class III), a calcium channel blocker (Class IV),and/or another anti-arrhythmic agent.

In some embodiments, the additional anti-arrhythmic agent is abeta-blocker and the beta-blocker is Acebutolol (SECTRAL®), Atenolol(TENORMIN®), Betaxolol (KERLONE®), Bisoprolol (ZEBETA®, ZIAC®),Carteolol (CARTROL®), Carvedilol (COREG®), Labetalol (NORMODYNE®,TRANDATE®), Metoprolol (LOPRESSOR®, TOPROL-XL®), Nadolol (CORGARD®),Nebivolol (BYSTOLIC®), Penbutolol (LEVATOL®), Pindolol (VISKEN®),Propanolol (INDERAL®), Sotalol (BETAPACE®), or Timolol (BLOCADREN®).

In one embodiment, the lithium, or salt thereof, is lithium carbonate(Li₂CO₃), and the beta-blocker is Metoprolol (LOPRESSOR®, TOPROL-XL®).In another embodiment, the lithium, or salt thereof, is lithium sulfate(Li₂SO₄), and the beta-blocker is Metoprolol (LOPRESSOR®, TOPROL-XL®).

In some embodiments, the composition comprises about 50 mg, about 100mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350mg, about 400 mg, about 450 mg, about 500 mg, or about 600 mg of thelithium, or salt thereof.

In some embodiments, the composition comprises about 2.5 mg, about 3.125mg, about 5 mg, about 6.25 mg, about 10 mg, about 12.5 mg, about 20 mg,about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about80 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about300 mg of the additional anti-arrhythmic agent.

In some embodiments, the compositions as disclosed herein are extendedrelease formulations.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows that treatment with lithium significantly reduces PVCs in apatient. A patient with PVCs as documented with a cardiac event monitorwas given lithium carbonate 300 mg per day (L_(i2)CO₃ 150 mg BID) incombination with metoprolol 150 mg per day for three different trials.Trial 1 was started on Aug. 23, 2019 and stopped on Jan. 1, 2020; Trial2 was started on Jan. 12, 2020 and stopped on Apr. 21, 2020; and Trial 3was started on May 8, 2020 and was ongoing at the time the instantapplication was filed. Within a few days, PVCs were reduced by about 90%and were reduced throughout the duration of lithium treatment.

DETAILED DESCRIPTION

The disclosure provides methods and compositions for treating heartconditions. In particular, the disclosure provides compositionscomprising lithium, or a salt thereof, either alone or in combinationwith at least one additional anti-arrhythmia agent, and methods fortreating heart conditions using such compositions.

In one aspect, the disclosure provides a method for treating and/orpreventing a heart condition, comprising administering an effectiveamount of lithium, or a salt thereof, to a subject in need thereof.

The term “subject” as used herein includes human and non-human animalsubjects.

A “heart condition” or “heart disorder” is any condition that wouldbenefit from treatment using the compositions as disclosed herein.“Heart disorder” and “heart condition” are used interchangeably hereinand include chronic and acute disorders or diseases, and can include,but are not limited to, coronary artery disease (CAD), atherosclerosis,heart attack, stroke, heart failure, arrhythmia, heart valve problems,and/or other cardiovascular disease (e.g., conditions that involvenarrowed or blocked blood vessels that can lead to a heart attack, chestpain, or stroke). In one embodiment, the heart condition can be anarrhythmia (i.e., a variation from a normal heart rate and/or heartrhythm that is not physiologically justified). In some embodiments, theheart condition can be an arrhythmia where electric impulses areinitiated too early and/or disrupt a heart's normal rhythm. In someembodiments, the heart condition can be an arrhythmia where electricimpulses originate from an area of the heart which is not considerednormal, or which are conducted in an area or pathway of the heart whichis not considered normal. In certain embodiments, the heart conditioncan include, but is not limited to, premature ventricular contraction(PVC), ventricular premature contraction (VPC), ventricular tachycardia,ventricular fibrillation, paroxysmal supraventricular tachycardia,accessory pathway tachycardia, AV nodal reentrant tachycardia,supraventricular tachycardia, premature atrial contractions, atrialfibrillation, atrial flutter, trigeminy, bigeminy, orWolff-Parkinson-White (WPW) syndrome. In certain embodiments, the heartcondition is atrial fibrillation or atrial flutter. In one embodiment,the heart condition is premature ventricular contraction (PVC) orventricular premature contraction (VPC). The heart conditions ofpremature ventricular contraction (PVC) and ventricular prematurecontraction (VPC) both refer to the same heart condition of extraheartbeats that begin in one of the heart's ventricles. The extra beatsdisrupt regular heart rhythm, and sometimes cause a subject to feel afluttering or skipped beat. Premature ventricular contraction (PVC) andventricular premature contraction (VPC) can be used interchangeably, andin some instances can also be referred to as premature ventricularcomplexes, ventricular premature beats, or ventricular extrasystoles.

The terms “treatment” or “treat” as used herein can refer to boththerapeutic treatment and prophylactic or preventative measures. Thosein need of treatment include those having heart disease as well as thoseprone to have the heart disease or those in which the heart disease isto be prevented. In certain embodiments, the compositions as disclosedherein is administered to a subject in need of treatment once per day,twice per day, three times per day, four times per day, or more. In someembodiments, the treatment is administered as an extended releaseformulation. The appropriate dose, frequency, and duration can bemodified to address the particular needs of a particular subject bytaking into account factors including, but not limited to, the age,gender, weight, and health of the subject; the severity, extent, andtype of the heart condition. In some embodiments, the length oftreatment can be less than 1 week to 12 months, or more than 12 months.In certain embodiments, treatment duration can be indefinite. In someembodiments, treatment duration can be until disease remission.

As used herein, the term “lithium” refers to the chemical elementlithium with the symbol Li and atomic number 3. In certain embodiments,lithium, or a salt thereof, can refer to any lithium composition thatresults in free lithium (Li⁺) in the serum of a subject whenadministered to the subject. In some embodiments, the lithium, or saltthereof, is lithium carbonate (Li₂CO₃), lithium sulfate (Li₂SO₄),lithium citrate (Li₃C₆H₅O₇), lithium acetate (C₂H₃LiO₂), lithium bromide(LiBr), lithium chloride (LiCl), lithium orotate (C₅H₃LiN₂O₄), orlithium gluconate (C₆H₁₁LiO₇).

The terms “effective amount” and “therapeutically effective amount” whenused in reference to a composition comprising lithium, or a saltthereof, refer to an amount or dosage sufficient to produce a desiredtherapeutic result. More specifically, a therapeutically effectiveamount is an amount of lithium, or a salt thereof, sufficient to preventand/or inhibit, for some period of time, one or more of the clinicallydefined pathological processes associated with the heart disease beingtreated. For example, in a patient with an arrhythmia, an effectiveamount would result in disappearance of or a decrease in the arrhythmiain the patient. In another example, in a patient with PVCs, an effectiveamount would result in disappearance of or a decrease in the number ofPVCs the patient experiences. In some embodiments, the therapeuticallyeffective amount of lithium can be considered a low dose (e.g., a lowdose when compared to a dose used as a psychiatric medication). Theeffective amount may vary depending on the lithium, or a salt thereof,dosages that are being used, and also depends on a variety of factorsand conditions related to the patient being treated and the severity ofthe heart disease. For example, if the lithium, or a salt thereof,composition is to be administered in vivo, factors such as the age,weight, and health of the patient as well as dose response curves andtoxicity data obtained in preclinical animal work would be among thosefactors considered in determining the effective amount ortherapeutically effective amount to be administered. The determinationof an effective amount or therapeutically effective amount of a givenpharmaceutical composition is well within the ability of those skilledin the art.

In certain embodiments, the effective amount of lithium comprises about5 mg to about 1800 mg, 10 mg to about 1200 mg per day, about 25 mg toabout 600 mg per day, about 50 mg to about 550 mg per day, about 100 mgto about 500 mg per day, about 150 mg to about 450 mg per day, about 200mg to about 400 mg per day, or about 250 mg to about 350 mg per day. Incertain embodiments, the effective amount of lithium comprises about 5mg per day, about 10 mg per day, about 15 mg per day, about 25 mg perday, about 50 mg per day, about 100 mg per day, about 150 mg per day,about 175 mg per day, about 200 mg per day, about 225 mg per day, about250 mg per day, about 275 mg per day, about 300 mg per day, about 325 mgper day, about 350 mg per day, about 375 mg per day, about 400 mg perday, about 425 mg per day, about 450 mg per day, about 475 mg per day,about 500 mg per day, about 525 mg per day, about 550 mg per day, about575 mg per day, about 600 mg per day, about 625 mg per day, about 650 mgper day, about 675 mg per day, about 700 mg per day, about 725 mg perday, about 750 mg per day, about 775 mg per day, about 800 mg per day,about 825 mg per day, about 850 mg per day, about 875 mg per day, about900 mg per day, about 925 mg per day, about 950 mg per day, about 975 mgper day, about 1000 mg per day, about 1050 mg per day, about 1100 mg perday, about 1150 mg per day, about 1200 mg per day, about 1250 mg perday, about 1300 mg per day, about 1350 mg per day, about 1400 mg perday, about 1450 mg per day, about 1500 mg per day, about 1550 mg perday, about 1600 mg per day, about 1650 mg per day, about 1700 mg perday, about 1750 mg per day, or about 1800 mg per day. In one embodiment,the effective amount of lithium comprises about 300 mg per day.

In some embodiments, the effective amount of lithium results in alithium (Li⁺) serum concentration in the subject in the range of about0.01 to about 1.2 mmol/L, about 0.02 to about 1.0 mmol/L, about 0.05 toabout 0.8 mmol/L, about 0.1 to about 0.6 mmol/L, about 0.2 to about 0.5mmol/L, about 0.25 to about 0.45 mmol/L, or about 0.1 to about 0.3mmol/L. In certain embodiments, the effective amount of lithium (Li⁺)serum concentration in the subject is about 0.01 mmol/L, about 0.02mmol/L, about 0.04 mmol/L, about 0.05 mmol/L, about 0.075 mmol/L, about0.1 mmol/L, about 0.2 mmol/L, about 0.25 mmol/L, about 0.3 mmol/L, about0.35 mmol/L, about 0.4 mmol/L, about 0.45 mmol/L, about 0.5 mmol/L,about 0.55 mmol/L, about 0.6 mmol/L, about 0.65 mmol/L, about 0.7mmol/L, about 0.75 mmol/L, about 0.8 mmol/L, about 0.85 mmol/L, about0.9 mmol/L, about 0.95 mmol/L, about 1.00 mmol/L, about 1.1 mmol/L, or1.2 mmol/L. In one embodiment, the effective amount of lithium resultsin a lithium serum concentration in the subject in the range of about0.1 to about 0.3 mmol/L.

In some embodiments, the effective amount of lithium, or salt thereof,is administered in a single dose or in multiple doses. In someembodiments, the effective amount of lithium, or salt thereof, isadministered as an extended release formulation. In certain embodiments,the effective amount of lithium, or salt thereof, is administered onetime per day, two times per day, three times per day, or four times perday. Dosing frequency will depend upon the pharmacokinetic parameters ofthe composition being used. Typically, a clinician will administer thecomposition until a dosage is reached that achieves the desired effect.In some embodiments, the composition is administered about every 24, 23,22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3,2, or 1 hours. In certain embodiments, the composition is administeredabout every 24, 12, 8, 6, or 4 hours. In yet another embodiment, thecomposition is administered every 8 or 12 hours. In some embodiments,the composition is administered 2, 3, 4, 5, or 6 times during at leastone 24 hour period. In another embodiment, the composition isadministered 2 or 3 times during at least one 24 hour period. In someembodiments, the composition is administered two times per day (BID),three times per day (TID), four times a day (QID), five times per day,or six times per day. In certain embodiments, the length of treatmentcan be less than 1 week to 12 months, or more than 12 months. Forexample, the length of treatment can be from about 1 week to about 4weeks, from about 2 weeks to about 6 weeks, from about 4 weeks to about8 weeks, from about 1 month to about 3 months, from about 2 months toabout 4 months, from about 3 months to about 6 months, from about 6months to about 12 months, or more than 12 months. In some embodiments,treatment duration can be until disease remission, for example, fromabout 1 month to about 24 months, or more than 24 months. In someembodiments, the subject is treated for about 1 month, about 2 months,about 3 months, about 4 months, about 5 months, about 6 months, about 7months, about 8 months, about 9 months, about 10 months, about 11months, about 1 year, about 2 years, or more than 2 years. In certainembodiments, the subject is treated indefinitely.

In some embodiments, the effective amount of lithium, or salt thereof,is administered orally, parenterally, transdermally, topically,transmucosally, by inhalation, by suppository, by buccal delivery, bysublingual delivery, by ophthalmic delivery, or by injection(subcutaneous injection, subdermal injection, intramuscular injection,depot administration, or intravenous injection). In certain embodiments,the effective amount of lithium, or salt thereof, is administeredorally. In some embodiments, the oral composition is an extended releasecomposition (i.e., designed to slowly release over an extended period oftime with a reduction of the peak/trough ratio compared to standardrelease). Extended release compositions can comprise ofsustained-release (SR), or controlled-release (CR) dosage.Sustained-release maintains drug release over a sustained period, butnot at a constant rate. Controlled-release maintains drug release over asustained period at a nearly constant rate. Sustained-release dosageforms are dosage forms designed to release a drug at a predeterminedrate in order to maintain a constant drug concentration for a specificperiod of time with minimum side effects.

In some embodiments, the methods disclosed herein further compriseadministering an additional anti-arrhythmic agent. As used herein,additional antiarrhythmic agents, refer to cardiac dysrhythmiamedications, and are a group of pharmaceuticals that are used tosuppress cardiac arrhythmias, for example, such as premature ventricularcontraction (PVC), ventricular premature contraction (VPC), ventriculartachycardia, ventricular fibrillation, paroxysmal supraventriculartachycardia, accessory pathway tachycardia, AV nodal reentranttachycardia, supraventricular tachycardia, premature atrialcontractions, atrial fibrillation, atrial flutter, trigeminy, bigeminy,or Wolff-Parkinson-White (WPW) syndrome. In certain embodiments, theadditional anti-arrhythmic agent is a sodium channel blocker (Class I),a beta-blocker (Class II), a potassium channel blocker (Class III), acalcium channel blocker (Class IV), and/or another anti-arrhythmicagent. In some embodiments, about 2.5 mg, about 3.125 mg, about 5 mg,about 6.25 mg, about 10 mg, about 12.5 mg, about 20 mg, about 25 mg,about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 80 mg, about100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg of theanti-arrhythmic agent can be administered to the subject.

In some embodiments, the additional anti-arrhythmic agent is abeta-blocker (Class II) and the beta-blocker is Acebutolol (SECTRAL®),Atenolol (TENORMIN®), Betaxolol (KERLONE®), Bisoprolol (ZEBETA®, ZIAC®),Carteolol (CARTROL®), Carvedilol (COREG®), Labetalol (NORMODYNE®,TRANDATE®), Metoprolol (LOPRESSOR®, TOPROL-XL®), Nadolol (CORGARD®),Nebivolol (BYSTOLIC®), Penbutolol (LEVATOL®), Pindolol (VISKEN®),Propanolol (INDERAL®), Sotalol (BETAPACE®), or Timolol (BLOCADREN®).

In some embodiments, the additional anti-arrhythmic agent is a sodiumchannel blocker (Class I) and the sodium channel blocker is Quinidine,Ajmaline, Procainamide, Disopyramide, Lidocaine, Phenytoin, Mexiletine,Tocainide, Encainide, Flecainide, Propafenone, or Moricizine.

In some embodiments, the additional anti-arrhythmic agent is a potassiumchannel blocker (Class III) and the potassium channel blocker isAmiodarone, Sotalol, Ibutilide, Dofetilide, Dronedarone, E-4031, orVernakalant.

In some embodiments, the additional anti-arrhythmic agent is a calciumchannel blocker (Class IV) and the calcium channel blocker is Verapamilor Diltiazem.

In some embodiments, the additional anti-arrhythmic agent is anotheranti-arrhythmic agent (for example, a Class V agent) and the anotheranti-arrhythmic agent is Adenosine, Digoxin, Magnesium citrate, orMagnesium sulfate.

In another aspect, the disclosure provides a composition comprisinglithium, or a salt thereof, and an additional anti-arrhythmic agent.

In certain embodiments, lithium, or a salt thereof, can refer to anylithium composition that results in free lithium (Li⁺) in the serum of asubject when administered to the subject. In certain embodiments of thisaspect, the lithium, or salt thereof, is lithium carbonate (Li₂CO₃),lithium sulfate (Li₂SO₄), lithium citrate (Li₃C₆H₅O₇), lithium acetate(C₂H₃LiO₂), lithium bromide (LiBr), lithium chloride (LiCl), lithiumorotate (C₅H₃LiN₂O₄), or lithium gluconate (C₆H₁₁LiO₇).

In some embodiments, the additional anti-arrhythmic agent is a sodiumchannel blocker (Class I), a beta-blocker (Class II), a potassiumchannel blocker (Class III), a calcium channel blocker (Class IV),and/or another anti-arrhythmic agent.

In some embodiments, the additional anti-arrhythmic agent is abeta-blocker and the beta-blocker is Acebutolol (SECTRAL®), Atenolol(TENORMIN®), Betaxolol (KERLONE®), Bisoprolol (ZEBETA®, ZIAC®),Carteolol (CARTROL®), Carvedilol (COREG®), Labetalol (NORMODYNE®,TRANDATE®), Metoprolol (LOPRESSOR®, TOPROL-XL®), Nadolol (CORGARD®),Nebivolol (BYSTOLIC®), Penbutolol (LEVATOL®), Pindolol (VISKEN®),Propanolol (INDERAL®), Sotalol (BETAPACE®), or Timolol (BLOCADREN®).

In some embodiments, the additional anti-arrhythmic agent is a sodiumchannel blocker (Class I) and the sodium channel blocker is Quinidine,Ajmaline, Procainamide, Disopyramide, Lidocaine, Phenytoin, Mexiletine,Tocainide, Encainide, Flecainide, Propafenone, or Moricizine.

In some embodiments, the additional anti-arrhythmic agent is a potassiumchannel blocker (Class III) and the potassium channel blocker isAmiodarone, Sotalol, Ibutilide, Dofetilide, Dronedarone, E-4031, orVernakalant.

In some embodiments, the additional anti-arrhythmic agent is a calciumchannel blocker (Class IV) and the calcium channel blocker is Verapamilor Diltiazem.

In some embodiments, the additional anti-arrhythmic agent is anotheranti-arrhythmic agent (for example, a Class V agent) and the anotheranti-arrhythmic agent is Adenosine, Digoxin, Magnesium citrate, orMagnesium sulfate.

In one embodiment, the lithium, or salt thereof, is lithium carbonate(Li₂CO₃), and the beta-blocker is Metoprolol (LOPRESSOR®, TOPROL-XL®).In another embodiment, the lithium, or salt thereof, is lithium sulfate(Li₂SO₄), and the beta-blocker is Metoprolol (LOPRESSOR®, TOPROL-XL®).

In some embodiments, the composition comprises about 5 mg, about 10 mg,about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg,about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about95 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 175mg, about 180 mg, about 190 mg, about 200 mg, about 225 mg, about 250mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg,about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700mg, about 1750 mg, or about 1800 mg of the lithium, or salt thereof.

In some embodiments, the composition comprises about 2.5 mg, about 3.125mg, about 5 mg, about 6.25 mg, about 10 mg, about 12.5 mg, about 20 mg,about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about80 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about300 mg of the additional anti-arrhythmic agent.

In some embodiments, the composition is a “pharmaceutical composition”or “therapeutic composition.” The terms “pharmaceutical composition” or“therapeutic composition” as used herein refer to a compound orcomposition capable of inducing a desired therapeutic effect whenproperly administered to a patient. For example, in a patient with anarrhythmia, administration of a therapeutic composition would result indisappearance of or a decrease in the arrhythmia in the patient. Inanother example, in a patient with PVCs, administration of a therapeuticcomposition would result in disappearance of or a decrease in the numberof PVCs the patient experiences.

The pharmaceutical composition can contain formulation materials formodifying, maintaining, or preserving, for example, the pH, osmolarity,viscosity, clarity, color, isotonicity, odor, sterility, stability, rateof dissolution or release, adsorption, or penetration of thecomposition. Suitable formulation materials include, but are not limitedto, amino acids (such as glycine, glutamine, asparagine, arginine, orlysine), antimicrobials, antioxidants (such as ascorbic acid, sodiumsulfite, or sodium hydrogen-sulfite), buffers (such as borate,bicarbonate, Tris-HCl, citrates, phosphates, or other organic acids),bulking agents (such as mannitol or glycine), chelating agents (such asethylenediamine tetraacetic acid (EDTA)), complexing agents (such ascaffeine, polyvinylpyrrolidone, beta-cyclodextrin, orhydroxypropyl-beta-cyclodextrin), fillers, monosaccharides,disaccharides, and other carbohydrates (such as glucose, mannose, ordextrins), proteins (such as serum albumin, gelatin, orimmunoglobulins), coloring, flavoring and diluting agents, emulsifyingagents, hydrophilic polymers (such as polyvinylpyrrolidone), lowmolecular weight polypeptides, salt-forming counterions (such assodium), preservatives (such as benzalkonium chloride, benzoic acid,salicylic acid, thimerosal, phenethyl alcohol, methylparaben,propylparaben, chlorhexidine, sorbic acid, or hydrogen peroxide),solvents (such as glycerin, propylene glycol, or polyethylene glycol),sugar alcohols (such as mannitol or sorbitol), suspending agents,surfactants or wetting agents (such as pluronics; PEG; sorbitan esters;polysorbates such as polysorbate 20 or polysorbate 80; triton;tromethamine; lecithin; cholesterol or tyloxapal), stability enhancingagents (such as sucrose or sorbitol), tonicity enhancing agents (such asalkali metal halides—preferably sodium or potassium chloride—or mannitolsorbitol), delivery vehicles, diluents, excipients and/or pharmaceuticaladjuvants (see, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES (18th Ed., A.R. Gennaro, ed., Mack Publishing Company 1990), and subsequent editionsof the same, incorporated herein by reference for any purpose).

In some embodiments, the compositions as disclosed herein can beadministered orally, parenterally, transdermally, topically,transmucosally, by inhalation, by suppository, by buccal delivery, bysublingual delivery, by ophthalmic delivery, or by injection(subcutaneous injection, subdermal injection, intramuscular injection,depot administration, or intravenous injection). In certain embodiments,the composition is administered orally. In some embodiments, the oralcomposition is an extended release composition (i.e., designed to slowlyrelease over an extended period of time). Extended release compositionscan comprise of sustained-release (SR), or controlled-release (CR)dosage. Sustained-release maintains drug release over a sustainedperiod, but not at a constant rate. Controlled-release maintains drugrelease over a sustained period at a nearly constant rate.Sustained-release dosage forms are dosage forms designed to release adrug at a predetermined rate in order to maintain a constant drugconcentration for a specific period of time with minimum side effects.

EXAMPLES

The Examples that follow are illustrative of specific embodiments of thedisclosure as provided herein, and various uses thereof. They are setforth for explanatory purposes only, and should not be construed aslimiting the scope of the disclosure as provided herein in any way.

Example 1: Treatment of PVCs Using Lithium

A patient with PVCs as documented with a cardiac event monitor was givenlithium carbonate 300 mg per day (Li₂CO₃ 150 mg BID; resulting in alithium serum level of about 0.2) in combination with metoprolol 150 mgper day. Within a few days, PVCs were reduced by about 90% (observationby EKG by physician/patient) for the duration of treatment with lithium.Three trials were performed with lithium carbonate (300 mg per day, 150mg BID) in combination with metoprolol 150 mg per day, and for eachtrial, PVCs were reduced by at least 90% for the duration of treatmentwith lithium. Within about one week of discontinuing lithium treatment,PVCs recurred. In each of three trials of lithium 150 mg twice daily,the number of PVCs was reduced within 12 days of starting the lithium by95% of the pre-lithium number of PVCs, and the number of PVCs wasreduced within 22 days of starting the lithium to 2 PVCs per minute ornone (note: 2 PVCs per minute is clinically insignificant for anyone).The rate of 2 PVCs per minute or none was maintained in the trials untilthe lithium was discontinued. The first trial was 109 days. The secondtrial was 43 days. In the third trial, the number of PVCs of less than 2per minute has been maintained for 54 days (as of Aug. 26, 2020). SeeFIG. 1.

Example 2: Treatment of PVCs Using Lithium

A patient with PVCs as documented with a cardiac event monitor is givenlithium (as lithium carbonate, lithium citrate or lithium sulphate) 300mg per day in an extended release formulation in combination withmetoprolol 50 mg per day—every twelve to twenty-four hours (e.g.,lithium carbonate 300 mg and metoprolol 50 mg once daily or lithiumcarbonate 150 mg and metoprolol 25 mg every twelve hours). Three daysafter treatment is initiated, a lithium blood level is obtained. Arepeat cardiac event monitor is performed fourteen days after startingtreatment. It is expected a patient's PVCs will be reduced by at least90%. If PVCs are not reduced, then the lithium dose is to be adjusted,and another blood level obtained after three days. A repeat cardiacevent monitor is performed in fourteen days. The process of doseadjustment, blood lithium levels, and cardiac event monitor is repeateduntil there is a 90% or greater reduction in PVCs. When that isobtained, another cardiac event monitor is done in one month. A furtherreduction in PVCs (to an amount of no more than 2 per minute) isexpected, but will not be necessary as long as the previous reduction of90% in PVCs is maintained.

All references cited in this application are expressly incorporated byreference herein.

What is claimed is:
 1. A composition consisting of a lithium salt, abeta-blocker, and one or more delivery vehicles, diluents, excipients,and/or pharmaceutical adjuvants.
 2. The composition of claim 1, whereinthe lithium salt is lithium carbonate (Li₂CO₃), lithium sulfate(Li₂SO₄), lithium citrate (Li₃C₆H₅O₇), lithium acetate (C₂H₃LiO₂),lithium bromide (LiBr), lithium chloride (LiCl), lithium orotate(C₅H₃LiN₂O₄), or lithium gluconate (C₆H₁₁LiO₇).
 3. The composition ofclaim 1, wherein the beta-blocker is Acebutolol, Atenolol, Betaxolol,Bisoprolol, Carteolol, Carvedilol, Labetalol, Metoprolol, Nadolol,Nebivolol, Penbutolol, Pindolol, Propanolol, Sotalol, or Timolol.
 4. Thecomposition of claim 1, wherein the lithium salt is lithium carbonate(Li₂CO₃), and the beta-blocker is Metoprolol.
 5. The composition ofclaim 1, wherein the composition comprises about 50 mg, about 100 mg,about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg,about 400 mg, about 450 mg, about 500 mg, or about 600 mg of the lithiumsalt.
 6. The composition of claim 1, wherein the composition comprisesabout 2.5 mg, about 3.125 mg, about 5 mg, about 6.25 mg, about 10 mg,about 12.5 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about50 mg, about 60 mg, about 80 mg, about 100 mg, about 150 mg, about 200mg, about 250 mg, or about 300 mg of the beta-blocker.
 7. Thecomposition of claim 1, wherein the composition is an extended releaseformulation.
 8. The composition of claim 4, wherein the compositioncomprises about 150 mg of Li₂CO₃ and about 25 mg of metoprolol.
 9. Thecomposition of claim 4, wherein the composition comprises about 300 mgof Li₂CO₃ and about 50 mg of metoprolol.
 10. A method for treatingand/or preventing a heart condition, comprising administering aneffective amount of the composition of claim 1 to a subject in needthereof.
 11. The method of claim 10, wherein the heart condition ispremature ventricular contraction (PVC), ventricular prematurecontraction (VPC), ventricular tachycardia, ventricular fibrillation,paroxysmal supraventricular tachycardia, accessory pathway tachycardia,AV nodal reentrant tachycardia, supraventricular tachycardia, prematureatrial contractions, atrial fibrillation, atrial flutter, trigeminy,bigeminy, or Wolff-Parkinson-White (WPW) syndrome.
 12. The method ofclaim 11, wherein the heart condition is premature ventricularcontraction (PVC) or ventricular premature contraction (VPC).
 13. Themethod of claim 10, wherein the composition results in a lithium (Li⁺)serum concentration in the subject in the range of about 0.1 to about0.3 mmol/L.
 14. The method of claim 10, wherein the composition isadministered one time per day, two times per day, three times per day,or four times per day.
 15. The method of claim 10, wherein thecomposition is administered orally, parenterally, transdermally,topically, transmucosally, by inhalation, by suppository, by buccaldelivery, by sublingual delivery, by ophthalmic delivery, or byinjection (subcutaneous injection, subdermal injection, intramuscularinjection, depot administration, or intravenous injection).
 16. Themethod of claim 10, wherein the subject is treated for about 1 month,about 2 months, about 3 months, about 4 months, about 5 months, about 6months, about 7 months, about 8 months, about 9 months, about 10 months,about 11 months, about 1 year, about 2 years, or more than 2 years. 17.The method of claim 10, wherein the subject is treated indefinitely.